A group of lymphocytes called natural killer (NK) cells kill many kinds of cells almost indiscriminately. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize surface molecules called major histocompatibility complex class I (MHC class I). A major goal of this project is to define the molecular basis of MHC class I recognition by the inhibitory receptors on NK cells. Another important question is how recognition of MHC class I by the receptor results in a negative signal transmitted to the NK cell. Although NK cells serve useful functions in immune responses against certain viruses and parasites, they are also dangerous, as they exhibit potent killing activity. Therefore, the mechanisms in place to prevent killing of normal cells by NK cells serve an essential function. It is important to understand how such regulation of NK activity is achieved. In addition, the regulation of NK cell activity by inhibitory receptors serves as a model to study other receptor systems that may use a similar mode of negative regulation. The experiments carried out under this project have identified a new region in the human genome that encodes several families of inhibitory receptors and defined specific amino acids in the killer cell inhibitory receptor that control recognition of MHC class I. A role for the heavy metal zinc, something unprecedented in receptors of the immunoglobulin superfamily, in the inhibitory signal delivered by the killer cell inhibitory receptor was established. Finally, it was discovered that different inhibitory receptors can block NK activation and that they use distinct signaling pathways to achieve inhibition.